2,3-Dihalopyridine compounds especially 2,3-dichloropyridine are important intermediates for fine chemical industry. The 2,3-dichloropyridine is an important raw material for the preparation of agrochemicals, pharmaceutical and other fine chemicals.
Several processes are reported in the prior art for the preparation of 2,3-dihalopyridine. The known processes differ from each other in respect of different process chemistry followed.
U.S. Pat. No. 4,515,953 and SU652177 disclose the liquid phase chlorination of pyridine or pyridine hydrochloride. The products obtained by this process include 2,3-dichloropyridine along with other polychlorinated pyridine mixture. A number of purification steps are required to extract 2,3-dichloropyridine.
U.S. Pat. No. 6,224,2631 and research article by Bay et al in J. Org. Chem. 1988, 53, 12, 2858-9 disclose a process for the preparation of 2,3-dichloropyridine by halogenetion of 2-chloro-3-nitropyridine with phenylphosphorous tetrachloride (PPTC) and benzenephosphorous dichloride (BPOD).
Shiao et al in Synthetic Communications, 1990, 20, 19, 2971-7 reported synthesis of halogenated 2-chloropyridines by transformation of halogenated 2-methoxypyridines under Vilsmeier-Haack conditions.
JP 01193246 discloses a process for the preparation of 2,3-dichloropyridine where 2,3,6-trichloropyridine formed during the process is reduced with hydrogen in the presence of Pd/C as catalyst.
Den Hertog et al in Rec. Des Tray. Chimi. Des Pays-Bas et de la Belgique, 1950, 69, 673-99; disclosed the preparation of several derivatives of chloropyridines. The research paper discloses a process for the preparation of 2,3-dichloropyridine by treating 2-chloro-3-aminopyridine with sodium nitrite, copper powder and hydrochloric acid. However, the article does not disclose clear process for extraction and purification of 2,3-dichloropyridine.
PCT application WO 2005070888 discloses a four-step process for preparing 2,3-dichloropyridine in which 3-amino-2-chloropyridine is contacted with an alkali metal nitrite in the presence of aqueous hydrochloric acid to form a diazonium salt; subsequently the diazonium salt is decomposed in the presence of copper catalyst wherein at least about 50% of the copper is in the copper (II) oxidation state, optionally in the presence of an organic solvent, to form 2,3-dichloropyridine. 3-amino-2-chloropyridine used in the process is prepared in three steps involving Hofmann rearrangement of nicotinamide to form 3-aminopyridine, contacting 3-aminopyridine with hydrochloric acid to form a 3-aminopyridine hydrochloric acid salt; chlorination of 3-aminopyridine hydrochloric acid salt with a chlorinating agent viz., chlorine or a mixture of hydrochloric acid and hydrogen peroxide to form 3-amino-2-chloropyridine.
CN 1807414 discloses a process for the preparation of 2,3-dichloropyridine. The process comprises of chlorinating 3-aminopyridine with oxydol at a molar ratio of 1:1 in concentrated hydrochloric acid at 6-8° C. for 1-2 h; diazotization of 2-chloro-3-aminopyridine by reacting with 30% sodium nitrite solution at <0° C. for 0.5-1 h; followed by chlorination with a mixture of cuprous chloride and concentrated hydrochloric acid at <0° C. for >30 min; heating reaction liquid to room temperature and extraction with 5-7 times (mass) of dichloromethane (twice) at room temperature; and decompressing and vaporizing the extract to remove the solvent to obtain 2,3-dichloropyridine.
JP 09227522 discloses a process for the separation of 2-chloro-3-aminopyridine from acidic aqueous solution containing 2-chloro-3-aminopyridine and 2,6-dichloro-3-aminopyridine, obtained by chlorination of 3-aminopyridine with chlorine in the presence of hydrochloric acid and FeCl3 at 40° C. for 1 h. The reaction mixture so obtained is mixed with toluene; adjusted to pH 0.5 with aqueous NH3, further adjusting the aqueous layer to pH 7 with aqueous NH3 and extraction with organic solvents to obtain pure 2-chloro-3-aminopyridine.
Krapcho and Haydar in Heterocyclic Communications, 1998, 4, 291-292 reported a process for the preparation of 2,3-dibromopyridine. The process involves temperature dependent displacements of chloride by bromide during the diazotization of 3-amino-2-chloropyridine, followed by addition of CuBr in 48% HBr, which results in high yield of 2,3-dibromopyridine. Additionally, the paper reported the preparation of 2,3-dibromopyridine via the hydrogenation reaction of 2,3,6-tribromopyridine and 1-methyl-4-nitrosobenzene on Pd/C.
Bouillon et al in Tetrahedron, 2002, 58, 17, 3323-3328 reported a three-step process for the preparation of 2,3-dibromopyridine from 2-amino-3-nitropyridine. The process involves diazotization of 2-amino-3-nitropyridine followed by addition of CuBr in 47% HBr to obtain 2-bromo-3-nitropyridine. The 2-bromo-3-nitropyridine so obtained is reduced with Fe and acetic acid to 3-amino-2-bromopyridine and subsequent diazotization to give 2,3-dibromopyridine.
Menzel et al in J. Org. Chem., 2006, 71, 5, 2188-2191 reported an improved method for the bromination of metalated haloarenes employing lithium, zinc transmetalation. In the prior processes the bromination of 2-bromo-3-lithium pyridine resulted in formation of 2,3-dibromopyridine in only 13% yield, whereas in the disclosed process after transmetalation to zinc, 2,3-dibromopyridine was formed in 90% yield.
Very few methods have been reported in the prior art for the preparation of 2,3-difluoropyridine. U.S. Pat. No. 5,498,807 and EP 667328 disclose process for the preparation of 2,3-difluoropyridine by reductive dechlorination of 2,3-difluoro-5-chloropyridine.
Finger et al in J. Org. Chem., 1962, 27, 3965-8 reported a process for the preparation of 2,3-difluoropyridine from 3-amino-2-fluoropyridine by diazotization of 3-amino-2-fluoropyridine with ethyl nitrite in fluoroboric acid. 3-amino-2-fluoropyridine in turn is prepared from 2-fluoropyridine-3-carboxamide by the Hofmann reaction. The yield of 2,3-difluoropyridine prepared by this process is very low (20%).
The dihalopyridine produced by the processes disclosed in the prior art is impure and requires several steps for extraction and isolation of the desired compound. In addition, the processes involve consumption of solvents in huge quantities, thereby making them costly and inappropriate for industrial production.
In light of the drawbacks of foregoing processes, and increasing demand for producing 2,3-dihalopyridines, there is a need to develop an alternate commercially and economically viable process for large scale manufacture of 2,3-dihalopyridine with high purity and yield. In addition the process should involve fewer purification steps and reduced quantity of solvents.
Therefore the present invention provides a solution to the aforesaid problems of the prior arts employing an improved process to produce dihalopyridine.